Introduction

All stages of the cystic fibrosis-related abnormal glucose tolerance (CF-AGT) spectrum are associated with increased morbidity and mortality which could be reduced by early detection and treatment (1-4). Despite, the oral glucose tolerance test (OGTT) with two blood glucose measurement time points from 10 years of age (yoa) is still the gold standard method according to current guidelines (5,6).

Aims & Methods

Our aim is to provide data on the usability and diagnostic value of a hybrid protocol for the detection of early AGT in children with CF (chwCF).
The Cystic Fibrosis Related Pancreatic Disorder Registry (CFRPDR) is a prospective registry involving chwCF (<18 yoa) undergoing our hybrid AGT-screening protocol. The screening protocol consists of a frequently-sampled three-hour OGTT with blood sampling in every 30 minutes. Those chwCF with more than two interim blood glucose levels higher than 11 mmol/l are further examined with postprandial capillary glucose monitoring. Screening is started as early as possible, in most cases before 10 yoa and repeated yearly.

Results

Currently 121 chwCF are involved in the registry from which we have analyzed the baseline data of the first 79. 74% of the chwCF were diagnosed with normal glucose tolerance (NGT) (0-18 yoa: 58, 0-6 yoa: 18, 7-12 yoa: 22, 13-18 yoa: 18), 15% with impaired glucose tolerance (IGT) (0-18 yoa: 12, 0-6 yoa: 3, 7-12 yoa: 5, 13-18 yoa: 4) and 11% with CF-related diabetes (CFRD) (0-18 yoa: 9, 0-6 yoa: 0, 7-12 yoa: 1, 13-18 yoa: 8) according to the current gold standard method. 60% of the chwCF were diagnosed with NGT (0-18 yoa: 47, 0-6 yoa: 14, 7-12 yoa: 17, 13-18 yoa: 16), 14% with indeterminate glycaemia (INDET) (0-18 yoa: 11, 0-6 yoa: 4, 7-12 yoa: 5, 13-18 yoa: 2), 15% with IGT (0-18 yoa: 12, 0-6 yoa: 3, 7-12 yoa: 5, 13-18 yoa: 4), and 11% with CFRD (0-18 yoa: 9, 0-6 yoa: 0, 7-12 yoa: 1, 13-18 yoa: 8) by frequently-sampled OGTT. After the postprandial capillary glucose monitoring 4 more diabetic chwCF were diagnosed, 3 of them had IGT and 1 of them had INDET according to their OGTT measurements. 39% (12 chwCF) of the AGT cases was diagnosed under 10 yoa with frequently sampled OGTT.

Conclusion

In our cohort CF-AGT is common even under 10 yoa, and 44% of the AGT cases would have been missed with current standard screening method. Therefore, guidelines need to be revised, and our hybrid AGT-screening protocol could be a potent alternative especially in low- and middle income countries where continuous glucose monitoring is less available.

References

1. Ode KL, Moran A. New insights into cystic fibrosis-related diabetes in children. Lancet Diabetes Endocrinol. 2013;1(1):52-8.
2. Kasim N, Khare S, Sandouk Z, Chan C. Impaired glucose tolerance and indeterminate glycemia in cystic fibrosis. J Clin Transl Endocrinol. 2021;26:100275.
3. Lewis C, Blackman SM, Nelson A, Oberdorfer E, Wells D, Dunitz J, et al. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med. 2015;191(2):194-200.
4. Ode KL, Chan CL, Granados A, Moheet A, Moran A, Brennan AL. Cystic fibrosis related diabetes: Medical management. J Cyst Fibros. 2019;18 Suppl 2:S10-s8.
5. Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33(12):2697-708.
6. Balfour-Lynn I. Clinical Guidelines: Care of Children with Cystic Fibrosis. UK: Royal Brompton and Harefield Hospital, NHS Trust Foundation; 2023.

Introduction

We aimed to assess the role of islet autoimmunity and family history of diabetes in the presence of CFRD in children with CF.

Aims & Methods

Data from 78 children were analysed from the CF-related Pancreatic Disorders Registry. Pancreatic islet autoantibodies (AABs) (glutamic acid decarboxylase (GAD), insulin (IAA), islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) were measured and family history of diabetes was collected in a cross-sectional manner. Family history of T1DM and T2DM was assessed using the criterion by Blackman et al., 2009 and Ferrat et al., 2020. Fischer, Kruskal-Wallis and Mann-Witney U test were used.

Results

Males comprised 55% of the study population, with a median age of 8.7 years (IQR: 5.4–14.0 years). 51 children were on CFTR modulator therapy. Children with CFRD were significantly older with a median age of 15.9 years (IQR: 7.5–18.7) for any AAB-positive CFRD compared to 8.0 years (IQR: 6.2–12.4) for non-CFRD, and 12.1 years (IQR: 9.9–13.5) for AAB-negative CFRD compared to 7.9 years (IQR: 4.0–13.6) for non-CFRD. Any AAB and single AAB positivity was significantly associated with CFRD (Table 1). Only two children reported T1DM in any relative. Family history of diabetes showed no association with CFRD. Any AAB positivity frequency was comparable among children with positive and negative family history (Blackman criteria p=0.136; Ferrat criteria p=0.133).

Conclusion

Islet AAB positivity is associated with CFRD in children with CF. CFRD, regardless of autoantibody status, is more common in older individuals, which aligns with known disease progression in cystic fibrosis. The usefulness of family history of diabetes as a prognostic factor in the development of CFRD is limited.

Introduction

Basic science results suggest that abnormalities of the endocrine pancreas in cystic fibrosis (CF) occur earlier than hitherto estimated (1). All stages of the abnormal glucose tolerance (AGT) spectrum are associated with declining pulmonary function and increased mortality which could be reduced by early recognition and treatment (2-4). Despite, screening for AGT is recommended only from 10 years of age (yoa) according to the current guidelines (5,6). Accurate knowledge of the prevalence of AGT and its subtypes is essential to develop a better screening strategy, therefore we conducted a systematic review and meta-analysis in the topic.

Aims & Methods

Our systematic review and meta-analysis (PROSPERO number: CRD42021282516) was conducted on studies that reported data on the prevalence of AGT or its subtypes in CF populations. Literature search was conducted in MEDLINE (via PubMed), Embase and Cochrane Register of Controlled Trials (CENTRAL). General and superselected populations (e.g.: pancreas exocrine insufficient, ΔF508 homozygous) were separately analyzed. Pooled proportions, risk and odds ratios with 95% confidence intervals (CI) were calculated in at least three age subgroups (pediatric, adult, mixed/unknown). One-stage dose-response random effect meta-analysis was used to assess the effect of age on CF- related diabetes (CFRD).

Results

The quantitative analysis included 457 studies and data from 520,544 patients. More than one third of children with CF (chwCF) were affected by AGT (0.31 [95% CI 0.25-0.37]), even under 10 yoa 0.33 [95% CI 0.23-0.44], and half of the adults with CF (awCF) had AGT (0.51 [95% CI 0.45-0.57]). The prevalence of prediabetes remained unchanged (impaired glucose tolerance in chwCF: 0.14 [95% CI 0.10-0.18]) vs. awCF: 0.19 [95% CI 0.14-0.25]), while the proportion of CFRD increased by age (<5 yoa: 0.005 [95% CI 0.0001-0.15]; 5-10 yoa: 0.05 [95% CI 0.01-0.27]; 10-18 yoa: 0.11 [95% CI 0.08-0.14]; >18 yoa: 0.27 [95% CI 0.24-0.30]).

Conclusion

CF-related AGT is common under 10 years of age. Reconsideration of the current guidelines and better awareness are needed for screening and treating AGT in CF, especially under 10 yoa, to delay the disease progression and maintain a better life quality.

References

1. Olivier AK, Yi Y, Sun X, Sui H, Liang B, Hu S, et al. Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets. J Clin Invest. 2012;122(10):3755-68.
2. Ode KL, Moran A. New insights into cystic fibrosis-related diabetes in children. Lancet Diabetes Endocrinol. 2013;1(1):52-8.
3. Lewis C, Blackman SM, Nelson A, Oberdorfer E, Wells D, Dunitz J, et al. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med. 2015;191(2):194-200.
4. Moran A, Pekow P, Grover P, Zorn M, Slovis B, Pilewski J, et al. Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial. Diabetes Care. 2009;32(10):1783-8.
5. Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, et al. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33(12):2697-708.
6. Balfour-Lynn I. Clinical Guidelines: Care of Children with Cystic Fibrosis. UK: Royal Brompton and Harefield Hospital, NHS Trust Foundation; 2023.

Introduction

CFTR modulators represent a groundbreaking therapeutic approach in cystic fibrosis (CF) management, targeting the underlying cause of the disease. These therapies have the potential to directly influence pancreatic beta-cell function and pathways involved in insulin secretion, thereby improving the glycemic status of people with CF (pwCF).

Aims & Methods

We aimed to evaluate the effect of CFTR modulator therapy on endocrine pancreatic function in patients with CF. A systematic search of three databases (PubMed, Embase, and CENTRAL) was conducted up to March 6, 2024, to identify studies examining the impact of CFTR modulators on glucose metabolism in pwCF comparing variables before and after CFTR modulator therapy. Outcomes of interest included measures from oral glucose tolerance tests (OGTT), continuous glucose monitoring (CGM), and glycated hemoglobin (HbA1c). Meta-analysis was initiated using random-effects models to estimate pooled mean differences (MD) and 95% confidence intervals (CIs). Subgroup analyses were created based on CFTR modulators and length of therapy. Covariate regression analyses were made to assess the relationship between therapy length and pooled MD. A p-value less than 0.05 was considered to be statistically significant. The study protocol was registered in PROSPERO with registration number CRD42024516198.

Results

Conclusion

Our results revealed an improvement in the 120-minute OGTT plasma glucose level in the elexacaftor/tezacaftor/ivacaftor subgroup. The absence of significant changes in other analyses may indicate that these medications could potentially slow or halt the deterioration of glucose metabolism. Further prospective studies are required to overcome the limitation of a relatively small patient number and to validate our findings.

Introduction

With chronic inflammation, recurrent infections, and dysbiosis, people with CF (pwCF) are predisposed to autoimmunity. However, the role of autoimmune-mediated pancreatic beta-cell damage is yet unclear in the development of cystic fibrosis-related abnormal glucose tolerance (CF-AGT).

Aims & Methods

We aimed to assess the prevalence of various islet autoantibodies (AABs) according to glucose tolerance and age and the risk associated with islet AAB positivity for developing CF-AGT. A systematic search across four databases (CENTRAL, Embase, PubMed, Web of Science) identified studies reporting on AABs against glutamic acid decarboxylase (GADA), insulin (IAA), islet cell (ICA), insulinoma-associated protein 2 (IA-2A), and zinc transporter 8 (ZnT8A) in pwCF (CRD42020155846). Prevalence and odds ratios (OR) were calculated with 95% confidence intervals (CI) using a random effects model with subgroup analysis by glucose tolerance and age.

Results

Conclusion

Introduction

Pancreatic fibrosis (PF) is a prominent histological feature of chronic pancreatitis and influences on vast majority of pancreatic disorders. So, PF early diagnosis gives a great opportunity to be a part of the strategy for preventing pancreatic diseases progression. It makes non-invasive PF assessment especially via biomarkers level measurement research perspective.

Aims & Methods

Aim was to evaluate the possibility of biomarkers levels measurement in PF grade assessment.
Methods. We measured interleukin-10 (IL-10) and interleukin-36 (IL-36), matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-9 (MMP-9), fibronectin (FN) and hyaluronic acid (HA) plasma levels from 165 patient who underwent surgery from April 2022 to February 2024 due to pancreatic tumors and advanced chronic pancreatitis. We included 69 (41.8%) male and 96 (58.2%) female patients, mean age was 57.91±13.5 (25-89). Serum levels of specified biomarkers were determined by enzyme immunoassay using commercial kits; data registration performed was carried out on a semi-automatic analyzer. PF morphological grade was assessed according to Klöppel & Maillet’s scoring system [1] and scaled into three grades: mild, moderate and severe PF.
This study was conducted within the healthcare research project “Assessment of pancreatic fibrosis as a prognostic factor for its diseases course” funded by Autonomous non-profit organization "Moscow Center for Innovative Technologies in Healthcare" administered by the Moscow Healthcare Department.

Results

Plasma FN (pFN) level was significantly (p=0.029) higher in patients with mild PF (pFN=110.7±72.7 μg/mL), than in patients with severe PF (pFN=74.9±32.8 μg/mL). The median pFN levels were significantly varied in groups with different grades of intralobular PF (p<0.05), but not in groups divided by perilobular PF grade (p>0.05). Moreover, pFN level significantly negatively correlated with PF integrative grade (Spearmen’s rho = -0.21, p=0.007). Regarding IL-10, IL36, MMP-1, MMP-9 and HA levels, there were no significant differences either in patients with different PF integrative grade, or in groups divided by perilobular and intralobular PF (p>0.05). We revealed no significant correlations between specified biomarkers levels and PF grade (p>0.05).

Conclusion

The FN serum level significantly decreased in patients with severe PF in contrast to patients with mild PF who had comparatively higher serum FN level. Oppositely, IL-10, IL36, MMP-1, MMP-9 and HA had shown no effect in PF grade assessment. It could be useful for noninvasive pancreatic fibrosis diagnosis and even for patients’ selection for advanced diagnostics.

References

1 Esposito I, Hruban RH, Verbeke C, et al. Guidelines on the histopathology of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and the European Pancreatic Club. Pancreatology. 2020;20(4):586-593. doi:10.1016/j.pan.2020.04.009

Introduction

Pancreatic fibrosis is a major histological feature of chronic pancreatitis (CP) as well as affects a course of vast spectrum of pancreatic disorders. Therefore, pancreatic fibrosis early diagnosis gives an invaluable opportunity to be a part of the strategy for preventing disease progression. So, it makes non-invasive pancreatic fibrosis evaluation techniques research perspective.

Aims & Methods

We aimed to clarify relationships between pancreatic fibrosis grade and results of multidetector computed tomography (MDCT). Results of contrast-enhanced 128-row MDCT from 43 patients who underwent surgery from April to December 2022 due to benign and malignant pancreatic tumors as well as advanced CP, mean age 56.8±14 (25-84) were analyzed. We calculated normalized contrast enhancement ratio during the pancreatic (PP)and venous phases (VP), as well as contrast enhancement ratio between VP and non-contrast MDCT Morphological signs of CP as well as pancreatic fibrosis grade were assessed by experienced pathologists according to Klöppel & Maillet’s scoring system [1] for the evaluation of the extent of fibrosis in CP.

Results

We received significant intergroup differences between mean values of normalized contrast enhancement ratios during PV and pancreatic duct epithelium metaplasia (p=0.02) and within morphological signs of pancreatic inflammation (p=0.017). There were differences in mean values of normalized contrast enhancement ratios during PV in groups divided by perilobular fibrosis grade (p=0.04). Unenhanced pancreas density value significantly differed in patients with pancreatic inflammation signs (33.1±11HU) and pancreatic duct epithelium metaplasia (33.1±8.1 HU) than in patients without both phenomena (40.8±5.9HU and 41.2±9.5HU, respectively), with p=0.01 and p=0.001, respectively. We revealed significant intergroup differences in unenhanced pancreas density value depending on intralobular fibrosis grade. Enhancement ratio values were also significantly different in groups divided by perilobular fibrosis grade (p=0.024).

Conclusion

Morphological signs of CP and pancreatic fibrosis like pancreatic tissue inflammation and pancreatic duct epithelium metaplasia as well as pancreatic peri- and intralobular fibrosis grade affect MDCT pancreas enhancement characteristics. It could be useful for noninvasive pancreatic fibrosis diagnosis and prognosis.

References

1. Esposito I, Hruban RH, Verbeke C, et al. Guidelines on the histopathology of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and the European Pancreatic Club. Pancreatology. 2020;20(4):586-593. doi:10.1016/j.pan.2020.04.009

Disclosure

This study was conducted within the healthcare research project “Assessment of pancreatic fibrosis as a prognostic factor for its diseases course” funded by Autonomous non-profit organization "Moscow Center for Innovative Technologies in Healthcare" administered by the Moscow Healthcare Department.